This competitive revision is in response to Notice Number (NOT-OD-09-058), Titled: "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". The cellular mechanisms that mediate the intoxicating and reinforcing effects of ethanol are not completely understood. However, considerable evidence supports the hypothesis that increased mesolimbic DA system activity is one of the important components of the reinforcing effects of many drugs of abuse, including ethanol. The hypocretins are recently identified neuropeptides that participate in the regulation of arousal and a variety of motivated behaviors. Emerging evidence indicates that the hypocretin system exerts a facilitatory influence on reward function and that these actions involve activation of dopamine neurons of the ventral tegmental area. For example blockade of hypocretin signaling reduces self-administration of ethanol and reduces the effects of ethanol on dopamine signaling. Given the potential that the hypocretin system regulates reward associated with drug abuse, the proposed studies will employ a multidisciplinary approach to investigate whether hypocretin regulates ethanol-induced changes in dopamine signaling. Studies will examine: 1) The extent to which the hypocretin system influences baseline and ethanol-induced levels of phasic dopamine signaling in the nucleus accumbens using in vitro fast scan voltammetry techniques;and 2) To what degree the hypocretin systems regulates baseline and ethanol-induced levels of tonic dopamine signaling in the nucleus accumbens using freely moving microdialysis. Completion of this work will provide pilot information on the extent to which hypocretin participates in reward processing, the extent to which these actions involve the mesolimbic DA system, and will offer insight into the neural mechanisms underlying the addiction process. Additionally this information and may help shape the foundations to generate novel pharmacotherapies for alcoholism. PUBLIC HEALTH RELEVANCE: The HCRT system may be an essential participant in the regulation of reinforcement properties of drugs of abuse, including ethanol. Understanding how this system modulates the neural correlates underlying ethanol-reinforcement processes, particularly as it relates to the mesolimbic DA system, could provide the basis for a rational drug design to treat addiction.